Substituted Quinolone Carboxylic Acids, Their Derivatives, Site of Action, And Uses Thereof

ABSTRACT

Substituted quinolone carboxylic acids and their derivatives are described. These compounds modulate the effect of γ-aminobutyric acid (GABA) via a novel site on the GABA A  receptor complex in a therapeutically relevant fashion and may be used to ameliorate CNS disorders amenable to modulation of the GABA A  receptor complex.

RELATED APPLICATION

This application claims priority to U.S. provisional application Ser.No. 60/380,641, filed on May 14, 2002.

FIELD OF THE INVENTION

This invention is in the field of medicinal chemistry. In particular,the invention relates to substituted quinolone carboxylic acids andtheir derivatives, which modulate, via a unique site, the effect ofγ-aminobutyric acid (GABA) on the GABA_(A) receptor complex in atherapeutically relevant fashion and may be used to ameliorate CNSdisorders amenable to modulation of the GABA_(A) receptor complex.

BACKGROUND OF THE INVENTION

GABA is the most abundant inhibitory neurotransmitter in the mammalianbrain. GABA controls brain excitability by exerting inhibitory functionson neuronal membranes by altering their permeability to specific ions.Binding of GABA to the GABA_(A)-type (GABA_(A)) receptor increases thepermeability of neuronal membranes to chloride ions (Cl−). In mostneurons the relative Cl− ion concentration is greater outside than theinside the membrane. Thus, selective permeability to Cl− initiated byGABA binding allows Cl− to flow down its electrochemical gradient intothe cell. The majority of fast inhibitory synaptic transmission is aresult of GABA binding to the GABA_(A) receptors. GABA_(A) receptors areubiquitously expressed throughout the CNS with almost all neuronsstaining for their presence. The GABA_(A) receptor is ahetero-pentameric protein structure of the nicotinic acetylcholinereceptor superfamily. Native GABA_(A) receptors are formed from at least19 related subunits. The subunits are grouped into α, β, δ, ε, π, and ρfamilies. The most prevalent combination of GABA_(A) receptors is astoichiometric combination of the 2×α, 2×β, and 1×γ subunits, with theremaining subunits relegated to substituting for the γ subunit duringspecific development expression or in highly specific brain regionlocalization. The adult brain predominately express the α1β2γ2 subunitcombination (60%) with the α2β3γ2 and α3βnγ2 subunits comprising themajority (35%) of the remaining receptors. The relative effects of GABAare influenced by the GABA_(A) receptor subunit expressed in a specificbrain region or neuronal circuit.

The neurophysiological effects of GABA result from a conformationalchange that occurs when GABA binds to the GABA_(A) receptor. TheGABA_(A) receptor and the associated ion channel complex (GRC) is aligand-gated ion channel which recognizes many compounds thatallosterically modulate the ability of GABA to bind to the GABA_(A)receptor. The allosteric modulators have distinct sites on the GRC.These sites are separate and unique from the site that recognizes GABA.The most widely studied and characterized class of allosteric modulatorof the GRC is that which interact with the benzodiazepine (BZ)-site.

Alternative sites for modulating the GRC have been described. Forexample, neuroactive steroids are non-hormonal steroids that bind andfunctionally modulate the GRC. The current role of neuroactive steroidsin GABA_(A) receptor pharmacology is supported by overwhelming evidence.Electrophysiological and biochemical techniques have confirmed thecapacity of neuroactive steroids to allosterically modulate the GRCthrough a unique site of action. Experimentally neuroactive steroidsexhibit a pharmacological profile similar, but not identical, to thebenzodiazepines. Neuroactive steroids produce anxiolytic,anticonvulsant, and sedative-hypnotic properties.

Certain antibacterial fluoroquinolone antibiotics have been implicatedin clinical reports as the cause of convulsions in humans (Ball P (1986)Journal of Antimicrobial Chemotherapy. 18 Suppl D 187-193; Simpson K J,Brodie M J (1985) Lancet ii. 161, 1985; Hori S, et al. (1987) Programand Abstracts of the Twenty-Seventh Interscience Conference onAntimicrobial Agents and Chemotherapy, New York 1987. Abstract 30, pg101). Experimentally, fluoroquinolones have been demonstrated to produceconvulsions and death in mice. Additionally, non-steroidalanti-inflammatory drugs (NSAIDs) and their by-products have beenreported to clinically and experimentally potentiate the convulsiveeffects of the fluoroquinolones. Concerns about the convulsantside-effects of fluoroquinolone antibacterial agents have led to aninterest in the interaction of fluoroquinolones with the GABA_(A)receptor. Convincing evidence has accumulated that suggests that theyinteract with the GRC to inhibit GABA action. Fluoroquinolonesantagonize [³H]muscimol and [³H]GABA binding to the GRC with highmicromolar potency. Electrophysiological studies have demonstrated thatfluoroquinolones alone weakly reduce GABA-evoked currents. As well,radioligand binding assays have shown that fluoroquinolones, incombination with NSAIDs, induce a conformational change in the GABA_(A)receptor-chloride channel complex that is indicative of apharmacologically relevant response consistent with functionalantagonism of GABA.

It is well-documented that modulation of the GRC can ameliorate anxiety,seizure activity, and insomnia. Thus, GABA and drugs that act like GABAor facilitate the effects of GABA (e.g., the therapeutically usefulbarbiturates and benzodiazepines (BZs) such as Valium) produce theirtherapeutically useful effects by interacting with specific modulatorysites on the GRC. None of the known drugs, however, are selectivelypotent at the α-2 subunit of the GABA receptor. Thus, they exhibitundesirable side effects of sedation, and in the case offluoroquinolones, convulsions. There is presently a need for GRCmodulators that are active without side effects.

SUMMARY OF THE INVENTION

The present invention relates to molecules that modulate the GRC withselective potency at the α-2 subunit of GABA to produce therapeuticallyuseful effects without side effects. The present invention furtherrelates to substituted quinolones represented by Formula I that act asenhancers of GABA-facilitated Cl⁻ flux mediated through the GABA_(A)receptor complex (GRC).

The invention also relates to methods of treating disorders responsiveto enhancement of GABA action on GABA receptors in a mammal byadministering an effective amount of a compound of Formula I and byactivation of the novel site which mediates the action of a compound ofFormula I as described herein. The novel site is defined by exclusioncriteria where a compound of Formula I does not act on known sites ofthe GRC which include the sites for GABA, benzodiazepines, neuroactivesteroids, t-butylbicyclophosphorothionate/picrotoxin, barbiturates,4′-chlorodiazepam, antibacterial quinolones, ivermectin,loreclezole/mefanamic acid, furosemide and propofol (E. R. Korpi, G.Grunder, H. Luddens, Progress Neurobiology 67:113-159, 2002).

The compounds of the present invention, being ligands for a unique siteon the GRC, are therefore of use in the treatment and/or prevention of avariety of disorders of the central nervous system. Such disordersinclude anxiety disorders, such as panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, animal andother phobias including social phobias, obsessive-compulsive disorder,stress disorders including post-traumatic and acute stress disorder, andgeneralized or substance-induced anxiety disorder; neuroses;convulsions; acute and chronic pain; cognitive disorders; insomnia;migraine; and depressive or bipolar disorders, for examplesingle-episode or recurrent major depressive disorder, dysthymicdisorder, bipolar I and bipolar II manic disorders, and cyclothymicdisorder.

Another aspect of the present invention is directed to the use of thesite that mediates the activity of compounds of Formula I as enhancersor inhibitors of GABA-facilitated Cl⁻ conductance mediated through theGABA_(A) receptor complex. Enhancement of GABA-mediated chlorideconductance is useful for the treatment and prevention of such disordersas anxiety and stress related disorders, depression and other affectivedisorders, epilepsy and other seizure disorders, insomnia and relatedsleep disorders, and acute and chronic pain. Inhibition of GABA-mediatedchloride conductance is useful for the treatment and prevention ofdisorders related to learning and memory such as mild cognitiveimpairment, age related cognitive decline, senile dementia, Alzheimer'sdisease, sleep disorders involving reduced wakefulness such asnarcolepsy and idiopathic hypersomnia.

Also, an aspect of the present invention is to provide a pharmaceuticalcomposition useful for treating disorders responsive to the enhancementGABA-facilitated Cl⁻ flux mediated through the GRC, containing aneffective amount of a compound of Formula I in a mixture with one ormore pharmaceutically acceptable carriers or diluents.

Compounds useful in the present invention have not been heretoforereported. Thus, the present invention is also directed to novelsubstituted quinolones having the structure of Formula I.

Further, the present invention is directed to ³H, ³⁵S, ³⁶Cl, ¹²⁵I, ¹³¹Iand ¹⁴C radiolabeled compounds of Formula I and their use as aradioligand for their binding site on the GRC.

Additional embodiments and advantages of the invention will be set forthin part in the description that follows, and in part will be obviousfrom the description, or may be learned by practice of the invention.The embodiments and advantages of the invention will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the potentiating effect of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (C3, 5 μM) on GABA (G, 10 μM) induced chloride currents inembryonic rat hippocampal neurons. These data demonstrate that C3 is apositive efficacy modulator of GABA-gated chloride channels.

FIG. 2 depicts receptor subunit selectivity and dose-dependent positiveefficacy of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydro-naphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3, CMP 3) versus diazepam (DZP) on GABA induced currents(I_(GABA)) in expressed human GABA_(A) receptors containing α₁β₂γ₂versus α₂β₂γ₂ subunits.

FIG. 3 depicts a comparison of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3) and Diazepam (DZP) on time spent in the dark in theMouse Light-Dark Transition Model of Anxiety. These data demonstratethat the anti-anxiety effects, as shown by the increase in the timespent in the dark, of compound 3 are comparable to that of DZP.

FIG. 4 depicts a comparison of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (CMP 3) and Diazepam (DZP) on punished responding as measured bythe number of licks during a 3 minute period in the Vogel Model ofAnxiety using 24 hour thirsted rats. These data demonstrate that theanti-anxiety effects, as shown by increased punished licking, ofcompound 3 are comparable to that of DZP.

FIG. 5 depicts an effect of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3) on 2 nM [³⁵S]TBPS binding to rat cortex in the absence(open circles) or presence or of 3 μM (closed circle) and 10 μM (closedsquare) of the GABA_(A) receptor antagonist (+)-bicuculline. These datademonstrate the absolute dependence of compound 3 on GABA for efficacyand that compound 3 is allosterically coupled to and does not actdirectly on the [³⁵S]TBPS site.

FIG. 6 depicts an effect of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3, closed circle), clonazepam (open circle) and5α-pregnan-3α-ol-20-one (3α,5α-P, open square) on 0.2 nM [³H}flunitrazepam binding to BZ receptors in rat cortex. These datademonstrate that compound 3 is allosterically coupled to and does notact directly on the BZ receptor.

FIG. 7 depicts an effect of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3, closed circle) and GABA (open circle) on 5 nM[³H]muscimol binding to the GABA_(A) receptor in rat cortex. These datademonstrate that compound 3 does not act directly on the GABA_(A)receptor.

FIG. 8 depicts an effect of 10 μM7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3, closed circle) or 100 nM 3α,5α-P (open square) on5α-pregnan-3α,20α-diol (5α,20α-diol, open circle) inhibition of 2 nM[³⁵S]TBPS binding to rat cortex. As predicted, increasing concentrationsof 5α,20α-diol (a partial agonist) antagonize the effect of 3α,5α-P (afull agonist). The inability of 5α,20α-diol to antagonize the effect ofcompound 3 demonstrates that compound 3 does not act directly on theneurosteroid site of the GRC.

FIG. 9 depicts the effect of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3) on 2 nM [³⁵S]TBPS binding to rat cortex in the absence(open circle) or presence of 30 μM norfloxacin (closed circle) and 100μM norfloxacin (closed square). The inability of norfloxacin to producea dose-dependent rightward parallel shift of the compound 3dose-response demonstrates that compound 3 does not act directly at thesame site as the antibacterial quinolone norfloxacin.

FIG. 10 depicts the dissociation of 2 nM [³⁵S]TBPS binding from ratcortex initiated by 10 μM7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3) in the absence (closed square) or presence (closedtriangle) of 30 μM pentobarbital. The ability of pentobarbital toaccelerate the dissociation of [³⁵S]TBPS binding indicates that compound3 and the barbiturate pentobarbital do not share a common site ofaction.

FIG. 11 depicts the effect of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3) on 2 nM [³⁵S]TBPS binding to rat cortex in the absence(open circle) or presence of 0.3 μM (closed circle), 1 μM (closedsquare) and 30 μM Ro5-4864 (4′-chlorodiazepam, closed triangle). Theinability of 4′-chlorodiazepam to produce a dose-dependent rightwardparallel shift of the compound 3/[³⁵S] TBPS dose-response curvedemonstrates that compound 3 does not act directly at the same site as4′-chlorodiazepam.

FIG. 12 depicts the dissociation of 2 nM [³⁵S]TBPS binding from mouseforebrain initiated by 10 μM7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3) in the absence (open circle) or presence (closedsquare) of 10 μM ivermectin. The ability of ivermectin to accelerate thedissociation of [³⁵S]TBPS binding indicates that compound 3 andivermectin do not share a common site of action.

FIG. 13 depicts the dissociation of 2 nM [³⁵S]TBPS binding from mouseforebrain initiated by 10 μM7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3) in the absence (open circle) or presence (closedsquare) of 10 μM mefenamic acid. The ability of mefenamic acid toaccelerate the dissociation of [³⁵S]TBPS binding indicates that compound3 and mefenamic acid do not share a common site of action.

FIG. 14 depicts the effect of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (compound 3) on 2 nM [³⁵S]TBPS binding to rat cerebellum in theabsence (open circle) or presence of 30 μM furosemide (closed circle).The inability of furosemide to produce a dose-dependent rightwardparallel shift of the compound 3 dose-response demonstrates thatcompound 3 does not act directly at the same site on the GRC as theloop-diuretic furosemide.

DETAILED DESCRIPTION OF THE INVENTION

The compounds useful in this aspect of the invention are substitutedquinolones represented by Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein:

R₁ is selected from the group consisting of hydrogen; an optionallysubstituted alkyl, amino, aryl and aralkyl;

each R₂ is selected from the group consisting of hydrogen and optionallysubstituted alkyl;

each R₃ is selected from the group consisting of hydrogen, optionallysubstituted alkyl; a group OR₁₁ and NR₁₂R₁₃;

R₅, R₇ and R₈ are independently selected from the group consisting ofhydrogen, an optionally substituted alkyl, and halogen;

R₉ and R₁₀ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, aralkyl, cycloalkyl andcycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom towhich they are attached to form a heterocyclic ring with the provisothat R₉ and R₁₀ are not both hydrogen at the same time;

R₁₁ is selected from the group consisting of hydrogen, an alkali metal,a negative charge and optionally substituted alkyl;

R₁₂ and R₁₃ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl andcycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atomto which they are attached to form a heterocyclic ring.

The invention also relates to quinolones represented by Formula II:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein:

R₁ is selected from the group consisting of hydrogen; an optionallysubstituted alkyl, and aralkyl;

each R₂ is selected from the group consisting of hydrogen and optionallysubstituted alkyl;

R₅, R₇ and R₈ are independently selected from the group consisting ofhydrogen, an optionally substituted alkyl, and halogen;

R₉ and R₁₀ are independently selected from the group consisting ofoptionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; orR₉ and R₁₀ are taken together with the nitrogen atom to which they areattached to form a heterocyclic ring.

Also, the invention relates to compounds of Formula III:

or a pharmaceutically acceptable salt, prodrug or solvate thereof,wherein:

R₁, R₂, R₅, R₇, R₈, R₉ are defined previously with respect to Formulae Iand II and n is an integer 0, 1, 2, 3 or 4.

For use in medicine, the salts of the compounds of Formula I-III will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulfuricacid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, orphosphoric acid. Furthermore, where the compounds of the invention carryan acidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts, e.g. sodium or potassium salts; alkalineearth metal salts, e.g. calcium or magnesium salts; and salts formedwith suitable organic ligands, e.g. quaternary ammonium salts.

The present invention includes within its scope prodrugs of thecompounds of Formula I above. In general, such prodrugs will befunctional derivatives of the compounds of Formula I which are readilyconvertible in vivo into the required compound of Formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least oneasymmetric center, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccenters, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

Useful halogen groups include fluorine, chlorine, bromine and iodine.

Useful alkyl groups include straight chain and branched C1-20 alkylgroups, more preferably, C5-20 alkyl groups. Typical C5-20 alkyl groupsinclude n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl,n-undecyl, n-dodecyl, n-tricedyl, n-tetradecyl, n-pentadecyl,n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl and eicosanylgroups.

Useful aryl groups are C₆₋₁₄ aryl, especially C₆₋₁₀ aryl. Typical C₆₋₁₄aryl groups include phenyl, naphthyl, anthracyl, indenyl, and biphenylgroups.

Useful arylalkyl groups include any of the above-mentioned C1-20 alkylgroups substituted with any of the above-mentioned C6-10 aryl groups.Useful arylalkyl groups include benzyl and phenethyl.

Useful cycloalkylalkyl groups include any of the above-mentioned C1-20alkyl groups substituted with any of the previously mentioned cycloalkylgroups. Examples of useful cycloalkylalkyl groups includecyclohexylmethyl and cyclopropylmethyl groups.

Useful halomethyl groups include C1-20 alkyl groups substituted with oneor more fluorine, chlorine, bromine or iodine atoms, includingfluoromethyl, difluoromethyl, trifluoromethyl and 1,1-difluoroethylgroups.

Useful hydroxyalkyl groups include C1-20 alkyl groups substituted byhydroxy, including hydroxymethyl, 1- and 2-hydroxyethyl and1-hydroxypropyl groups.

Useful alkoxy groups include oxygen substitution by one of the C1-20alkyl groups described above.

Useful alkylthio groups include sulfur substitution by one of the C1-20alkyl groups described above including decyl- and hexadecylthio groups.

Useful alkylamino and dialkylamino are —NHR₉ and —NR₉R₁₀, wherein R₉ andR₁₀ are C1-20 alkyl groups.

Useful dialkylaminoalkyl groups include any of the above-mentioned C1-20alkyl groups substituted by any of the previously mentioned dialkylaminogroups.

Useful alkylthiol groups include any of the above-mentioned C1-20 alkylgroups substituted by a —SH group.

A carboxy group is —COOH.

An amino group is —NH₂.

The term heterocyclic is used herein to mean saturated or wholly orpartially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclicring system, which consists of carbon atoms and from one to fourheteroatoms independently selected from the group consisting of O, N,and S, wherein the nitrogen and sulfur heteroatoms can be optionallyoxidized, the nitrogen can be optionally quaternized, and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring, and wherein the heterocyclic ring can besubstituted on carbon or nitrogen if the resulting compound is stable.Examples include, but are not limited to pyrrolidine, piperidine,piperazine, morpholine, 1,2,3,4-tetrahydroquinoline, and the like.

Optional substituents on R₁ to R₁₃ include any one of halo,halo(C₁₋₂₀)alkyl, aryl, cycloalkyl, C₁₋₂₀ alkyl, aryl(C₁₋₂₀)alkyl,cycloalkyl(C₁₋₂₀)alkyl, hydroxy(C₁₋₂₀)alkyl, amino(C₁₋₂₀)alkyl,alkoxy(C₁₋₂₀)alkyl, amino, hydroxy, thiol, alkoxy, and C₁₋₂₀ alkylthiolgroups mentioned above. Preferred optional substituents include: halo,halo(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, alkoxy and amino.

The synthesis of compounds of Formula I where R₇=Cl and R₁₀=H can beaccomplished by reacting a primary amine, R₉NH₂, in1-methyl-2-pyrrolidinone (NMP) with7-chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(2, commercially available from Acros, see Scheme 1).

Examples of R₉NH₂ include substituted benzylamines, substitutedphenethylamines, 3-phenylaminopropane, 1-aminoindan and1-amino-1,2,3,4-tetrahydronaphthlene.

For the synthesis of compounds of Formula I with groups other than ethyland cyclopropyl at R₁, the 6-fluoro-7-chloro starting material (8) canbe prepared as in Scheme 2 starting from commercially available2,4-dichloro-5-fluorobenzoyl chloride (4, Lancaster Synthesis).

Examples of R₁NH₂ include 2-fluoroethylamine, optionally substitutedbenzylamines and optionally substituted phenethylamines. Other methodsfor assembling the quinolone ring can be used as described in Atkins, etal, Org. Process Res. & Develop. (1997), 1, 185-197.

In Vitro Binding Assay 1

[³⁵S]TBPS binding assay. The cortex from male Sprague-Dawley rats(weighing 160-200g) was removed immediately after decapitation anddissected over ice. A P₂ homogenate was prepared for binding assay aspreviously described (Gee K W Phenylquinolines PK 8165 and PK 9084allosterically modulate [³⁵S]t-butylbicyclophosphorothionate binding toa chloride ionophore in rat brain via a novel Ro5 4864 site. J.Pharmacol. Exp. Ther. 240:747-753, 1987). The tissue was homogenized in0.32M sucrose (J.T. Baker Chemical Co., Phillipsburg, N.J., USA) with aTeflon-coated pestle, followed by centrifugation at 1,000×g for 10 min.The supernatant was collected and centrifuged at 9,000×g for 20 min. Theresultant P₂ pellet was resuspended in ice-cold 50 mM sodium potassiumphosphate (J.T. Baker) buffer (pH 7.4) containing 200 mM NaCl (J.T.Baker) and used immediately in binding assays. A 2 nM concentration of[³⁵S]TBPS (86 Ci/mmol; New England Nuclear, Boston, Mass., USA) wasincubated with 100 μl of tissue homogenate (10% w/v) in the presence orabsence of 5 μM GABA (Sigma Chem. Co., St. Louis, Mo.) and 5 μl aliquotsof test drug dissolved in dimethyl sulfoxide (Sigma Chem. Co.) (≦10 μlof solvent used in all assays). At the concentration (≦1%) used,dimethyl sulfoxide had no effect on specific [³⁵S]TBPS binding. Allassays were brought to a final volume of 1 ml with 50 mM sodiumpotassium phosphate buffer (pH 7.4) containing 200 mM NaCl. Non-specificbinding was defined as binding in the presence of 2 μM TBPS (NEN,Boston, Mass.) and accounted for ˜30% of the total binding. Assays wereterminated after a 90-min steady-state incubation at 25° C. by rapidfiltration through glass fiber filters (no. 32; Schleicher & Schuell,Keene, N.H.). The dissociation kinetics of [³⁵S]TBPS binding weremeasured by initiating dissociation by the addition of a saturatingconcentration of a known inhibitor of [³⁵S]TBPS binding or a testcompound to tissue homogenates pre-equilibrated with 2 nM [³⁵S]TBPSfollowed by filtration at various time points after the addition of theknown inhibitor or test compound. Allosteric modulators of the knowninhibitor or test compound will modify the rate of dissociation underthese conditions whereas agents acting at common site will not affectthe rate. Filter-bound radioactivity was quantified by liquidscintillation spectrophotometry. The data were evaluated by nonlinearregression (GraphPad, Inc., San Diego, Calif.) to obtain IC₅₀(concentration at which half-maximal inhibition of radioligand occurs)values.

In Vitro Binding Assay 2

[³H]Flunitrazepam binding: assays were carried out under identicalconditions, using an identical tissue preparation, as those used in the[³⁵S]TBPS binding assays with the exception that 1 μM GABA was added toall samples instead of 5 μM GABA. [³H]Flunitrazepam, 0.2 nM (75 Ci/mmol,New England Nuclear, Boston, Mass.) was used to label BZ sites.Non-specific binding is defined as binding in the presence of 1 μMclonazepam. The data were evaluated by nonlinear regression to obtainIC₅₀ and EC₅₀ values.

In Vitro Binding Assay 3

[³H]Muscimol binding assay: The cortex from male Sprague-Dawley rats(160-200g) was removed immediately after euthanizing and dissected overice. The tissue was homogenized in 15 vol of 0.32M sucrose followed bycentrifugation for 10 min at 1000×g. The supernatant was transferred toa 38 mL polycarbonate tube (Beckman Instruments, Palo Alto Calif.) andcentrifuged at 20,000×g for 20 min. The membrane pellet was resuspendedin 10 vol of dH₂O and centrifuged at 8,000×g for 20 min. The resultingpellet was washed with dH₂O once and with Na⁺-free assay buffer (40 mMKH₂PO₄, 100 mM KCl, pH 7.4). The pellet was resuspended in 35 mL ofNa⁺-free assay buffer, incubated at 37° C. for thirty minutes and thencentrifuged 31,000×g for twenty minutes. The final pellet wasresuspended in 10 vol of Na⁺-free assay buffer. Protein concentration ofmembrane preparations was ˜1 mg/mL by BCA reagent protein assay.Aliquots of membrane suspension (100 μL) were incubated in Na⁺-freeassay buffer with 5 mM [³H]muscimol (25 Ci/mmol, New England Nuclear,Boston, Mass.) and 5 μL of dimethylsulfoxide (DMSO) or drug dissolved inDMSO. The final volume of the incubation medium was 1 mL. Non-specificbinding was defined as binding in the presence of 1 mM GABA. Afteraddition of membranes, tubes were briefly vortexed and incubated at 4°C. in the dark. The incubation was terminated after 60 min by rapidfiltration through glass fiber filters followed by three washes withice-cold assay buffer. Filter-bound radioactivity was quantified by LSCafter an overnight extraction. The data were evaluated by nonlinearregression to obtain IC₅₀ and EC₅₀ values.

Electrophysiological Assay 1.

Pregnant Sprague-Dawley rats, incubating embryos of 17-19 daysgestation, were killed by cervical dislocation. The embryos were removedunder aseptic conditions and the brains quickly excised and placed inHank's balanced salt solution (HBSS, Gibco) at ambient room temperature(18-22° C.). The hippocampi were dissected out and chopped intofragments (˜2 mm³) and transferred into an enzyme solution containing(in mM): NaCl 116, KCl 5.4, NaHCO₃ 26, NaH₂PO₄ 1, CaCl₂ 1.5, MgSO₄ 1,EDTA 0.5, glucose 25, cysteine 1, and papain 20 U/ml (Sigma) andincubated at 37° C., 5% CO₂, 100% relative humidity for 1 hr. Tissuefragments were washed in HBSS containing 1 mg/ml of bovine serum albumin(BSA) and 1 mg/ml of ovomucoid (both Sigma). Tissue was transferred intoa further 3-4 ml of this solution and gently triturated into a singlecell suspension using a fire-polished Pasteur pipette. The single cellsuspension was layered on to 5 ml HBSS containing 10 mg/ml of BSA and 10mg/ml of ovomucoid and centrifuged at 100×g for 10 min. The supernatantwas discarded and the cells resuspended in 3-4 ml of glutamine-freeminimal essential media (MEM, Gibco) supplemented with heat-inactivatedfetal calf serum (5% v/v Gibco), heat-inactivated horse serum (5% v/vGibco), streptomycin and penicillin (50 μg/ml and 5000 i.u./ml,respectively), glutamine and glucose (final concentrations 2 mM and 20mM [Gibco and BDH] respectively). Approximately 1-2×10⁵ cells wereplated out on to each 35 mm (Falcon “Primaria”) tissue culture dishwhich contained ˜1 ml of the sera-enriched MEM. The plates weremaintained at 37° C., in 5% CO₂, and 100% relative humidity until usedin electrophysiological studies. Background proliferation ofnon-neuronal elements was suppressed with cytosine arabinoside (10 μM,Sigma) for 48 hr 7 days after initial dissociation.

Agonist evoked membrane currents were recorded from hippocampal neuronsusing the whole cell configuration of the patch-clamp technique. Neuronswere voltaged clamped at −60 mV using a List electronics L/M EPC-7converter head stage and amplifier. Cells were perfused with an external(bath) recording solution containing (in mM): NaCl 140, KCl 2.8, MgCl₂2, CaCl₂ 1 and HEPES-NaOH 10 (pH 7.2). Tetrodotoxin (TTX, 0.3 4M) wasincluded in the recording solution to suppress synaptic activity. Theexternal solution was delivered (at ˜2 ml/min) by a Watson-Marlow flowpump via non-sterile tubing, which was connected to a plastic cannula(tip dia 1 mm). The input cannula was mounted on a Prior®micromanipulator and was positioned in close (<1 mm) proximity to thecell under study. Bath solution was withdrawn from the dish via a 19Gneedle connected by flexible tubing to an aquarium suction pump. Therecording electrode was filled with an internal solution composed of (inmM): CsCl or KCl 140, MgCl₂ 2, CaCl₂ 0.1, EGTA 1.1 (free Ca²⁺˜10⁻⁸ M),HEPES-NaOH 10, and ATP-Mg²⁺ 2. The recording electrodes were fabricatedfrom glass hematocrit tubes (Kimble sodalime tubes 73811) on a NarishigePB7 two stage electrode puller. Electrodes were coated within 100 μm ofthe tip with “Sylgard” (Dow Corning) and fire polished just before use.Agonists were applied locally to the soma of a voltage-clamped neuron bypressure ejection (1.4 Kpa, 10-80 msec, 0.1-0.033 Hz) from the tip of amodified recording pipette using a Picospritzer H device (General ValveCorporation). The agonist-containing pipette was positioned within 0.1mm of the cell using a Leitz micromanipulator. The microscope andmicromanipulators were all mounted on a vibration-free isolation airtable (Wentworth) placed inside a Faraday cage. Agonist-evoked wholecell currents were monitored on a storage oscilloscope (Tektronix 2212),recorded, after digital pulse code modulation (frequency response 14kHz, Sony PCM 701), and displayed on Multitrace (Electromed) pen chartrecorder (frequency response 0.5 kHz). All drugs, other than theagonists, were applied to cells via the superfusion system.Agonist-evoked whole cell currents were measured at their peak.Responses in the presence of drugs expressed as the arithmetic mean ±SEMof responses in the absence (control) or drugs.

Electrophysiology Assay 2

GABA_(A) subunit transfected HEK cells are maintained at 37° C. and 5%CO₂ using Dulbecco's Modified Eagle's Medium with L-glutamine and nosodium pyruvate (Irvine Scientific #9031, Irvine Calif.) andsupplemented with 10% fetal bovine serum (Irvine Scientific #3000), 10U/ml hygromycin B (Calbiochem #400051), and an antibiotic cocktailconsisting of 100 μg/ml streptomycin sulfate, 0.25 μg/ml amphotericin B,100 units/ml penicillin G (Gibco 15240-096, Gaithersburg Md.). Cells arepassed by 2× wash with phosphate buffered saline (PBS) pH 7.4 and liftedusing 1× trypsin/EDTA solution in PBS (0.5 mg/ml trypsin, 0.2 mg/mlEDTA, Irvine Scientific #9342) when confluency reaches ˜90%.

GABA_(A) subunit transfected HEK cells are grown to 70% confluency onslide. Cells are transferred to a bath that is continuously perfusedwith extracellular saline. The extracellular medium contained 145 mMNaCl, 3 mM KCl, 1.5 mM CaCl₂, 1 mM MgCl₂, 5.5 mM d-glucose, and 10 mMHEPES, pH 7.4 at an osmolarity of 320-330 mosM. Recordings are performedat room temperature using the whole cell patch clamp technique. Thepatch pipette solution contained 147 mM N-methyl-D-glucaminehydrochloride, 5 mM CsCl, 5 mM K₂ATP, 5 mM HEPES, 1 mM MgCl₂, 0.1 mMCaCl₂, and 11.1 mM EGTA, pH 7.2, at an osmolarity of 315 mosM.Pipette-to-bath resistance is typically 3-5 Mohms. Cells are voltageclamped at −60 mV, and the chloride equilibrium potential wasapproximately 0 mV. Drugs are dissolved in extracellular medium andrapidly applied to the cell by local perfusion. A motor drivenmulti-channel switching system exchanged solutions in approximately 20ms.

In Vivo Pharmacology Vogel Conflict

Adult male rats are randomly divided into groups of 6 rats/group.Animals were deprived of water overnight (24 hr). Food was freelyavailable at time of thirsting. Thirty minutes after injection (i.p.) oftest drug, positive control drug (diazepam, 1 mg/kg), or vehicle controlrats are placed in a square Plexiglas box containing a stainless steelbottom connected to one side of a drinkometer circuit. At the other sideof the drinkometer circuit a water bottle, placed so the drink tubeextends into the Plexiglas box, is connected. When a subject drinks fromthe bottle the circuit is closed and an electric shock is delivered atthe tube after seven licks are recorded. The number of licks in a 3 minsession is recorded. Anti-anxiety agents will increase the number ofshocks the animal is willing to endure to acquire water.

Light-Dark Transition

Male NSA mice (25-30 g) are used. The apparatus consists of anopen-topped box divided into small and large area by a partition thathas a hole at floor level. The small compartment is painted black andthe large compartment white. The white compartment was illuminated withlight and the black compartment with red light. The time spent in thelight versus dark compartments and the number of transitions betweencompartments is recorded during a 5 min test session. Vehicle or testcompounds are administered 30 min prior to the test. Diazepam isadministered (i.p.) at 2 mg/kg as the positive control. Anti-anxietyagents will reduce the time the animals will spend in the darkcompartment and increase the number of transitions between the twocompartments.

Carriers

In addition to administering the compound as a raw chemical, thecompounds of the invention may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries, whichfacilitate processing of the compounds into preparations, which can beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which can be administered orally and which can be used forthe preferred type of administration, such as tablets, dragees, andcapsules, and also preparations which can be administered rectally, suchas suppositories, as well as suitable solutions for administration byinjection or orally, contain from about 0.01 to 99 percent, preferablyfrom about 0.25 to 75 percent of active compound(s), together with theexcipient.

Suitable excipients are, in particular, fillers such as saccharides, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings that, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions maybe used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetylcellulose phthalate orhydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigmentsmay be added to the tablets or dragee coatings, for example, foridentification or in order to characterize combinations of activecompound doses.

Other pharmaceutical preparations, which can be used orally, includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain the active compounds in the form of granules, whichmay be mixed with fillers such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds are preferablydissolved or suspended in suitable liquids, such as fatty oils, orliquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations, which can be used rectally,include, for example, suppositories, which consist of a combination ofone or more of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatin rectal capsules, which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400). Aqueous injection suspensions maycontain substances, which increase the viscosity of the suspension, andinclude, for example, sodium carboxymethyl cellulose, sorbitol, and/ordextran. Optionally, the suspension may also contain stabilizers.

EXAMPLE 17-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

To a suspension of7-chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(Acros; 6.02 g, 22.3 mmol) in 30 mL of 1-methyl-2-pyrrolidinone wasadded neat 1,2,3,4-tetrahydro-1-aminonaphthalene (20 mL, 20.5 g, 140mmol) drop-wise via syringe. The resulting light yellow mixture wasplaced in an oil bath at 140° C. for 17 h. Once at rt, the reaction wasadded to 120 mL of an aq. 2N HCl solution and ice. The solid that formedwas isolated by filtration, washed with an aq. 2N HCl solution (120 mL),water (2×100 mL), MeOH (3×50 mL) and EtOAc (50 mL). The solid thatremained was then recrystallized from MeOH (1400 mL). The yellow needlesthat formed were isolated and washed with methanol (2×50 mL). This solidwas then subjected to flash column chromatography. A solution of thesolid in 35 mL of 4% MeOH/CH₂Cl₂ was added to 16 cm of silica in a 5 cmdia. column. Elution with 1 L of 7.5% and 500 mL of 10% MeOH/CH₂Cl₂ gave968 mg (11%) of the title compound as a yellow solid, mp 246-247° C. ¹HNMR (400 MHz, DMSO-d₆) δ15.14 (s, 1H), 8.66 (s, 1 H), 7.80 (s, 1H), 7.63(s, 1H), 7.32 (d, 1H, J=7.7 Hz), 7.26-7.16 (m, 3H), 4.90 (s, 2 H), 4.33(q, 2H, J=7.2 Hz), 2.92-2.80 (m, 2H), 2.12-2.00 (m, 2H), 1.92-1.86 (m,2H), 1.60 (t, 3H, J=7.2 Hz). MS (M+Na)⁺ 419. Anal Calcd. forC₂₂H₂₁ClN₂O₃+0.25 HCl: C, 65.08; H, 5.28; Cl, 10.92; N, 6.90. Found: C,65.09; H, 5.33; Cl, 10.85; N, 6.81.

The following compounds were prepared by using the method describedabove:

-   (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(6-methoxy-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(5-methyl-1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;

7-Chloro-1-ethyl-6-(2-phenethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid. The reaction was performed as in Example 1 except that the crudereaction mixture was diluted with EtOAc giving the desired compound as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 15.15 (br s, 1H), 8.64 (s, 1H),7.63 (s, 1H), 7.58 (s, 1H), 7.37-7.33 (m, 2H), 7.29-7.24 (m, 3H), 4.68(t, 1H, J=5.4 Hz), 4.31 (q, 2H, J=7.3 Hz), 3.59 (q, 2H, J=6.4 Hz), 3.03(t, 2H, J=6.9 Hz), 1.58 (t, 3H, J=7.3 Hz);

7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid, ¹H NMR (400 MHz, CDCl₃) δ 15.10 (s, 1H), 8.62 (s, 1H), 7.77 (s,1H), 7.62 (s, 1H), 7.33 (d, 1H, J=7.0 Hz), 7.25-7.17 (m, 3H), 4.91 (brs, 2H), 3.99 (s, 3H), 2.86 (m, 2H), 2.11-2.01 (m, 2H), 1.91-1.87 (m,2H);

-   7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-cyclopropyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-[4-fluoro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(2-phenylcyclopropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(2-phenylcyclopropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(-naphthylethyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid;-   7-Chloro-1-ethyl-6-(1-naphthylmethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid and-   7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic    acid.

EXAMPLE 27-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-(n-propyl)carboxamide

To a solution of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (37 mg, 0.093 mmol) in 5 mL of CHCl₃ at −10° C. was added neat Et₃N(30 μL, 22 mg, 0.22 mmol) and benzyl chloroformate (17 mL, 20 mg, 0.117mmol). After stirring cold for 45 m, neat propylamine (10 μL, 7.2 mg,0.122 mmol) was added via syringe to the reaction at −20° C. Thereaction was then allowed to warm to rt over 2 h and added to 7 mL eachof a 10% aq. K₂CO₃ solution and CHCl₃. The organic layer was separatedand washed with water (2×10 mL), dried (Na₂SO₄), filtered andconcentrated to dryness. The residue was taken up in CH₂Cl₂ and added to10 cm of flash silica gel in a 2 cm dia. column. Elution with 100%CH₂Cl₂ (100 mL) and 2.5% MeOH/CH₂Cl₂ (200 mL) gave 37 mg (91%) of thetitle compound as a yellow solid.

The following compounds were prepared by using the general method givenin Example 2:

-   7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-(2-phenethyl)carboxamide;-   7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-(2-dimethylaminoethyl)carboxamide    and-   7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-(pyridylmethylamino)carboxamide.

EXAMPLE 37-Chloro-1-(2-phenethyl)-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

a. Ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate. Amixture of ethyl 3,3-dimethylaminoacrylate (3.10 g, 21.6 mmol) andN,N-diisopropylethylamine (8.0 mL, 5.94 g, 45.9 mmol) was stirred at rtand a solution of 2,4-dichloro-5-fluorobenzoyl chloride (4.92 g, 21.6mmol) was added drop-wise via addition funnel over 20 m. The cloudyyellow solution that formed was placed in an oil bath at 85-90° C. After3 h, the mixture that formed was filtered and the solid was washed withbenzene. The dark filtrate was concentrated and the residue wastriturated with hexanes (50 mL). The solid that didn't dissolve wascollected and washed with hexanes (20 mL). The resulting solid waspartitioned between water and EtOAc. The EtOAc layer was washed withwater (3×25 mL), brine, dried (Na₂SO₄), filtered and concentrated to 5.0g (69%) of the desired compound.

b. Ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(2-phenethylamino)acrylate.A suspension of ethyl2-(2,4-dichloro-5-fluorobenzoyl)-3-(dimethylamino)acrylate (1.014 g,3.03 mmol) in 10 mL of EtOH was treated with neat phenethylamine (0.4mL, 386 mg, 3.19 mmol) added drop-wise via syringe. After stirring at rtfor 75 m, the mixture that formed was filtered and the solid was washedwith EtOH leaving 620 mg (50%) of the acrylate as a white solid.

c. Ethyl7-chloro-6-fluoro-1-(2-phenethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.To a solution of ethyl2-(2,4-dichloro-5-fluorobenzoyl)-3-(2-phenethylamino)acrylate (656 mg,1.60 mmol) in 1.5 mL of DMF was added solid K₂CO₃ (227 mg, 1.64 mmol).The resulting mixture was placed in an oil bath at 130° C. for 16 h.Once at rt, the reaction was added to water. The gummy solid that formedwas partitioned between water and EtOAc. The aq. layer was extractedwith EtOAc (2×10 mL). The pooled organic layers were washed with water(2×15 mL), brine and dried (Na₂SO₄). The solvent was removed in vacuo,giving 572 mg (96%) of the desired quinolone.

d.7-Chloro-6-fluoro-1-(2-phenethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid. A solution of ethyl7-chloro-6-fluoro-1-(2-phenethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(516 mg, 1.38 mmol) in 5.7 mL of an aq. 6 N HCl solution was placed inan oil bath at 113° C. for 3 h 40 m. Once at rt, the mixture wasfiltered and washed with water (2×10 mL) to give 466 mg (98%) of theacid as a solid.

e.7-Chloro-1-(2-phenethyl)-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid. Using the procedure described in Example 1, the title compound wasisolated in 6% yield.

By using the method in Example 3, the following compounds were prepared:7-Chloro-1-(benzyl)-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid.

EXAMPLE 4 Modulation of [³⁵S]TBPS Binding in Rat Cortex by7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid

The ability of7-chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid to inhibit the binding of [³⁵S]TBPS was determined according to thepreviously described method. The following compounds in Tables 1 and 2were also tested for their ability to inhibit or enhance [³⁵S]TBPSbinding to rat cortex.

TABLE 1 Inhibition or Enhancement of [³⁵S]TBPS binding by 6-SubstitutedQuinolones

% Inhibition or{Enhancement} of 2 nM TBPSin Rat Cortex at 10 μM

 0

10

62

26

50

40

65 (IC₅₀ = 4.0 μM)

38

70 (IC₅₀ = 2.7 μM)

69 (IC₅₀ = 1.1 μM)

74 (IC₅₀ = 1.7 μM)

29

50

35

 0

65

84 (IC₅₀ = 2.0 μM)

26

12

65

11

 0

31

{17}

IC₅₀ = 1.4 μM

66

72

85 (IC₅₀ = 2.7 μM)

59

32

[32]

TABLE 2 Inhibition of [³⁵S]TBPS binding to rat cortex by QuinoloneAmides and Esters

% Inhibition or{Enhancement} of 2 nM TBPSin Rat Cortex at 10 μM

86 (IC₅₀ = 1.5 μM)

79

65

IC₅₀ = 880 nM

1-13. (canceled)
 14. A method for the treatment of CNS disorders amenable to amelioration via modulation of the GABA_(A) receptor complex, comprising the step of: administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring.
 15. The method of claim 14, wherein the compound comprises a compound having the Formula II:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring.
 16. The method of claim 14, wherein the compound comprises a compound having the Formula III:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁, R₂, R₅, R₇, R₈, R₉ are as defined in claim 1; n is an integer 0, 1, 2, 3 or
 4. 17. The method of claim 16, wherein n is
 2. 18. The method of claim 16, wherein R₁ is alkyl, R₂, R₅ and R₈ are hydrogen and R₇ is halogen.
 19. The method of claim 14, wherein the compound is: 7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro (phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 20. A method for the treatment of anxiety and related disorders, which comprises administering to a patient in need of such treatment an effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl, or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 21. A method for the treatment of convulsions, which comprises administering to a patient in need of such treatment an effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 22. A method for the treatment of insomnia, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl, a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 23. A method for the treatment of major depressive and bipolar disorders, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃. R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 24. A method for the treatment of chronic or acute pain, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 25. A method for the treatment of neuroses, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 26. A method for the treatment of withdrawal-induced convulsions from substance abuse which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl, or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are, H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 27. A method for the treatment of phobias, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 28. A method for the treatment of panic disorders, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl, a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl, R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 29. A method for the treatment of generalized anxiety disorders which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 30. A method for the treatment of obsessive-compulsive disorders which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl: R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 31. A method for the treatment of post traumatic and acute stress disorders, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen, an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 32. A method for the treatment of migraine pain, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen, an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl, a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 33. A method for the treatment of bipolar manic disorders, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 34. A method for the treatment of cognition deficit disorders, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen, R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, —R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 35. A method for the treatment of disorders such as anxiety and stress related disorders, depression and other affective disorders, epilepsy and other seizure disorders, insomnia and related sleep disorders, and acute and chronic pain by enhancement of chloride conductance through the site mediating the action of compound of Formula I

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen, an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl; a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen; R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et, with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 36. A method for the treatment of disorders related to learning and memory such as mild cognitive impairment, age related cognitive decline, senile dementia, Alzheimer's disease, sleep disorders involving reduced wakefulness such as narcolepsy and idiopathic hypersomnia by inhibition of chloride conductance through the site mediating the action of compound of Formula I

or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: R₁ is selected from the group consisting of hydrogen; an optionally substituted alkyl, and aralkyl; each R₂ is selected from the group consisting of hydrogen and optionally substituted alkyl; each R₃ is selected from the group consisting of hydrogen, optionally substituted alkyl: a group OR₁₁ and NR₁₂R₁₃; R₅, R₇ and R₈ are independently selected from the group consisting of hydrogen, an optionally substituted alkyl, and halogen, R₉ and R₁₀ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, cycloalkyl and cycloaralkyl; or R₉ and R₁₀ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; R₁₁ is selected from the group consisting of hydrogen, an alkali metal, a negative charge and optionally substituted alkyl; R₁₂ and R₁₃ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, aralkyl, aryl, cycloalkyl and cycloaralkyl; or R₁₂ and R₁₃ are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; with the proviso that when R₉ and R₁₀ are taken together to form a piperazinyl ring, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, R₅ and R₈ are H, then R₁ is not Et; with the further proviso that when R₉ and R₁₀ taken together to form 4-methylpiperazine, R₇ is Cl, R₃ is OR₁₁, R₁₁ is H, and R₅ and R₈ are H, then R₁ is not Et; and with the further proviso that when R₉ and R₁₀ are taken together to form a morpholinyl ring, R₁, R₂, R₅, R₇, R₈ are H, R₃ is NR₁₂R₁₃ and either R₁₂ or R₁₃ is H, the other is not n-butyl.
 37. The method of claim 20 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 38. The method of claim 21 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 39. The method of claim 22 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 40. The method of claim 23 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 41. The method of claim 24 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 42. The method of claim 25 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 43. The method of claim 26 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 44. The method of claim 27 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 45. The method of claim 28 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 46. The method of claim 29 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 47. The method of claim 30 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 48. The method of claim 31 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 49. The method of claim 32 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 50. The method of claim 33 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 51. The method of claim 34 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 52. The method of claim 35 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof.
 53. The method of claim 36 wherein the compound is 7-Chloro-1-ethyl-6-1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (R)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; (S)-7-Chloro-1-ethyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(1-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-aminoindanyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(benzylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(phenethyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[3-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[2-methoxy(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-bromo(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-[4-chloro(phenethylamino)]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(3-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(4-phenylbutyl-2-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenylpropylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 7-Chloro-1-ethyl-6-(2-phenoxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or 7-Chloro-1-methyl-6-(1,2,3,4-tetrahydronaphthyl-1-amino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; or a pharmaceutically acceptable salt, prodrug or solvate thereof. 